The production of leukotrienes (LTs) is an important physiological response to immunological challenge. Leukotrienes C.sub.4, D.sub.4 and E.sub.4 (LTC.sub.4, LTD.sub.4 and LTE.sub.4) play a very significant role in the pathophysiology of several inflammatory diseases, especially chronic asthma and allergic rhinitis. LTC.sub.4 synthase is a glutathione-S-transferase which uniquely catalyzes the synthesis of LTC.sub.4 from LTA.sub.4 and reduced glutathione. LTC.sub.4 is a peptidoleukotriene having a cysteinyl-glycine (Cys--Gly) moiety which is derivatized with gamma-glutamic acid. Cleavage of the gamma-glutamic acid residue yields LTD.sub.4 containing the dipeptide Cys--Gly. Dipeptidase cleavage of the glycine residue from LTD.sub.4 yields LTE.sub.4.
LTC.sub.4 and LTD.sub.4 are potent bronchoconstrictors which act on smooth muscle cells in the lung. These peptidoleukotrienes are released endogenously in the lung tissue of asthmatics upon exposure to specific allergens and induce many of the phenomena associated with asthma, including pulmonary smooth muscle contraction, vasoconstriction, increased vascular permeability, slow mucociliary clearance, and increased mucus secretion, when these leukotrienes are administered exogenously.
Because the glutathione-S-transferase, LTC.sub.4 synthase, is essential for the production of LTC.sub.4 from which are derived LTD.sub.4 and LTE.sub.4, and because elevated LTC.sub.4 and LTD.sub.4 levels are associated with potent bronchoconstriction in response to immunological challenge, it would be very desirable to be able to identify LTC.sub.4 synthases inhibitor compounds which can selectively inhibit production of LTC.sub.4, LTD.sub.4 and LTE.sub.4.
LTC.sub.4 synthase is a membrane-bound glutathione S-transferase activity that is distinct from all other glutathione S-transferases and appears to be exclusively committed to the biosynthesis of LTC.sub.4. Human LTC.sub.4 S is composed of a single 18-kDa polypeptide that is functionally active as a homodimer. The purification to homogeneity and partial amino acid sequence have been reported for human LTC.sub.4 S from the human monocytic leukemia cell line THP-1 by D. W. Nicholson et al., Proc. Natl. Acad. Sci. USA 90, 2015-2019 (1993). However, the complete amino acid sequence and nucleotide sequence for LTC.sub.4 synthase were heretofore unknown. Moreover, the purification is difficult and the scale-up in production necessary to obtain large quantities of LTC.sub.4 synthase necessary for large scale LTC.sub.4 inhibitor screening assays is problematic.
It would be very advantageous to provide DNAs which encode human LTC.sub.4 synthase and to provide expression vectors comprising such DNAs, which vectors, when introduced into suitable host cells, direct the production of recombinant human LTC.sub.4 synthase. It would also be very beneficial to be able to utilize recombinant human LTC.sub.4 synthase, and host cells capable of making recombinant LTC.sub.4 synthase, in screening assays to detect compounds capable of inhibiting LTC.sub.4 synthase.